MAO-A / MAO-B and behaviour

[knockout_mice]

I am not new to the forums, but this is my first post, so if i make any mistakes, please forgive me.

I found a few interesting articles about the connection between MAO and behaviour.

MAO (monoamine oxidase) A and B are key isoenzymes that degrade biogenic and dietary amines. MAO A preferentially oxidizes serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), whereas MAO B preferentially oxidizes phenylethylamine (PEA). Both forms can oxidize dopamine (DA). However, the substrate specificity overlap and the in vivo function of these two isoenzymes is not clear. Recently, we have shown that MAO A and B knock-out (KO) mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A KO mice have elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar to men with a deletion of MAO A. In contrast, MAO B KO mice do not exhibit aggression and only levels of PEA are increased. Both MAO A and B KO mice show increased reactivity to stress. Taken together, these results suggest that MAO A and B have distinctly different roles in monoamine metabolism. Further, these mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

http://www.ncbi.nlm.nih.gov/pubmed/10389141

Platelet monoamine oxidase (MAO) activity is highly genetically regulated and has repeatedly been associated with temperament [15]. Low platelet MAO-B activity correlates with personality traits such as sensation seeking, impulsivity and monotony avoidance. Platelet MAO-B has also been associated with deviant behavior such as type II alcoholism, which is a risk factor in adult ADHD. MAO-B is considered to be a marker of serotonergic capacity [15] and low activity has previously been associated with ADHD [16]. Two key genes expressing proteins of major importance for serotonergic activity are the genes encoding the serotonin transporter (5-HTT) and the monoamine oxidase A (MAO-A) enzyme. Both of these genes have functional promoter polymorphisms that have been shown to be associated with behavior: the 5-HTT LPR and the MAO-A VNTR [17,18]. A hypothesis which currently gains increasing experimental support is that prenatal serotonin levels are of importance for the development of the central serotonergic system. This hypothesis is supported by molecular genetic [19], pharmacological [20] and brain imaging studies [21].

http://www.biomedcentral.com/1471-244X/8/28

selegiline: http://www.mindandmuscle.net/articles/chemically-correct-l-deprenyl-part-ii-by-andrew-novick/

I would be really glad if someone could send me the full text of the former article, because I'm really interested in those "differences in [...] behaviour".

Last week, I started using standard doses (5mg/d) of selegiline (l-deprenyl), which is an irreversible MAO-B inhibitor (with a 40d half-life of inhibition/mao-b recovery) and I noticed a lot of things, like overall mood-lift, motivation, creative/artistic idea flow, vivid dreams, but on the other hand a little sleepiness, and "prickness" / sudden bursts of anger. Also, everything seems more "3D". I'm afraid, that the high dopamine concentrations will downregulate my dopamine receptors so selegiline will lose its effects and in the long run I will fall back to my "old" possible-ADHD, unmotivated state. It seems to work just like methylphenidate, but without the anxiety, comedown and peripheral side effects. I haven't tried amphetamine, but excitotoxicity doesn't sound very fun. Any personal experiences on long-term selegiline? Or studies on DAR receptor availability / tolerance after sel. treatment?

I'm also interested in traditional MAOIs. What do you think, how does it affect behaviour / aggressiveness? Are they good for motivation?

knockout_mice

 

[sekio]

The abstract tells you what the "differences in behaviour" are.

MAO A KO mice have elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar to men with a deletion of MAO A. In contrast, MAO B KO mice do not exhibit aggression and only levels of PEA are increased. Both MAO A and B KO mice show increased reactivity to stress. Taken together, these results suggest that MAO A and B have distinctly different roles in monoamine metabolism. Further, these mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

MAO-A inhibition seems much more predisposed to side effects like anger, compulsion, hypertension et cetera - it is well known by now that polymorphisms or deletions in the MAO-A gene can be linked to anger outbursts ("warrior gene").

Given that both isoforms of MAO degrade dopamine, I would not be worried about downregulation of dopamine receptors - the overall raise in DA is going to be diffuse and rather modest when compared to euphorigenic drugs like e.g. amphetamine or cocaine. (see abstract - MAOB knockout produces only rise in brain phenethylamine) However the overall rise in n/t levels, modest as it is, will likely going be supressed somewhat by your body's autoreceptor systems over time (as in e.g. SSRI therapy) so things should "smooth out" somewhat. This does not neccesarily mean that it will lose efficacy - more likely, side effects will gradually diminish.

Segelegine is much different from methylphenidate in its MOA, it should actually be a lot more effective in the long run as it will not deplete brain monoamine stores anywhere near as much as DRA/DRIs. From the anecdotes I have heard it seems that selective MAOB inhibitors are pretty good for some people who dont respond to other therapies.

As for "classical" double-whammy MAO A/B inhibitors, those need very careful dietary/drug intake modifications. Many drugs can kill or severely fuck you up when mixed with strong MAO inhibitors, and even things like eating cheese can lead to hypertensive crises. To tell a tale of efficacy, however, the first MAO inhibitor (isoniazid I think) was developed as anti-tuberculosis drugs and it was only when doctors noticed patients were "inappropriately happy" that it was discovered to be an antidepressant. Must be pretty good shit to keep you smiling with a severe respiratory infection!

 

[knockout_mice]

Thanks for your reply, sekio!

The abstract tells, that the main behavioural difference between MAO-A and MAO-B deficit is the aggressiveness, but it doesn't tell what's the difference between low MAO-B levels and normal activity. There should be a lot of other things...
Maybe there's an explanation of the "increased reactivity to stress".

Well, it tells that there is only an increase in the levels of PEA, but I found a conflicting study.

The (-)deprenyl-induced increase of the dopaminergic tone in the striatum was proved by measurements of the activity of the nigrostriatal dopaminergic neuron. Whereas the striatum of untreated rats contained 52.7 +/- 1.6 nmole/g dopamine (DA) and the turnover rate (TRDA) was found to be 13.7 +/- 1.3 nmole/g/hr, the striatum of rats pretreated with 0.25 mg/kg (-)deprenyl daily for 28 days contained significantly higher amount of DA (81.77 +/- 5.7 nmole) and the turnover rate increased significantly to 24.44 +/- 1.1. Using the Glowinski-Iversen preparation we found that from the striata of untreated rats 200.0 +/- 25.8 pmole/g/min DA was released to KCl stimulation, whereas the amount of DA released to stimulation from the striata of rats pretreated with (-)deprenyl for 3 weeks increased significantly to 1452.2 +/- 183.1 pmole/g/min.

http://ukpmc.ac.uk/abstract/MED/2828537

And according to this study, (-)deprenyl also inhibits dopamine autoreceptors, and reuptake of dopamine. Keeping this in mind, should I be taking any kind of dopamine precursor supplementation (for example L-dopa) for the maximum efficacy? I read it somewhere, that (-)deprenyl for parkinson's was just as efficient by itself as when combined with L-dopa, but clearly I don't take it for that condition...

Another interesting read:

However, increases in locomotor activity and dopa accumulation induced by deprenyl were almost totally prevented by pretreatment with the microsomal liver enzyme inhibitor proadifen hydrochloride (50 mg/kg, i.p., 30 min), indicating that metabolites of the drug are of pharmacological significance for deprenyl's central actions. Furthermore, administration of l-methamphetamine, a major metabolite of deprenyl, affected spontaneous locomotor activity and striatal dopa formation and the firing rate of dopamine-containing neurons in the substantia nigra within the same magnitude as deprenyl itself when given in doses relevant to the formation of l-methamphetamine from deprenyl.

http://jpet.aspetjournals.org/content/259/2/841.short

knockout_mice

 

[sekio]

Keeping this in mind, should I be taking any kind of dopamine precursor supplementation (for example L-dopa) for the maximum efficacy?

No, it's a waste of money. Increase dietary protein intake if anything.

The implication of the last cited paper is that L-methamphetamine is actually responsible for the dopamine-elevating effects seen in man/mice, not deprenyl itself.

 

[knockout_mice]

Update: Selegiline lose its efficacy after 3-4 months. The positive effects diminished, but the side effects stayed. I got gradually more and more irritable / anxious and developed some kind of muscle twitching. But when it worked, it was a perfect motivation enhancer.

k_m

 

[Abject]

Must be pretty good shit to keep you smiling with a severe respiratory infection!

lol'd

 

[AlphaMethylPhenyl]

Results will vary person-by-person.

I found it excellent, except for the debilitating insomnia.

 

[Black]

Keeping this in mind, should I be taking any kind of dopamine precursor supplementation (for example L-dopa) for the maximum efficacy? I read it somewhere, that (-)deprenyl for parkinson's was just as efficient by itself as when combined with L-dopa, but clearly I don't take it for that condition...

i wouldn't take l-dopa for this purpose. with morbus parkinson l-dopa certainly leads to downregulation and also accelerates dopamine neuron cell death (which limits its efficacy as medication to a few years, so it is avoided for as long as possible even though it's the best medication against the symptoms available).

i always thought mao b was the main enzyme responsible for dopamine breakdown (hence seleginine for morbus parkinson)...

 

[dopamimetic]

i always thought mao b was the main enzyme responsible for dopamine breakdown (hence seleginine for morbus parkinson)...

Me too. But the use in parkinson's could also be cause of mao b sometimes oxidizing things to reactive radicals- think this is one reason for neurotoxicity of dopamine releasers in high dosage.

But yes, have tried selegiline for myself and it did conversely really not feel like a DA increase. Found it useless, unfortunately. Could be that I just felt the l-meth metabolite, but at 5mg the possibility for this is low.

On the other side, the selective mao a inhibitor moclobemide was at least as useless either, at up to 600 mg/d.

 

[red22]

Here's a pertinent question. I'm looking at this study in an attempt to understand selegiline's power. It states that doses of 0.3 to 3 mg/kg inhibited MAO-A significantly (in addition to MAO-B), however it later states that only the very highest dose reduced the formation of DOPAC and HVA. DOPAC is a dopamine metabolite and HVA is a metabolite of dopamine and norepinephrine..as far as I can tell. A reduction in these metabolites would mean greater drug action in the brain. My question is what are the implications of this? Note that the article refers to selegiline as deprenyl.

--
Deprenyl was effective in inhibiting the deamination of [¹⁴C]-PEA (type B MAO activity) at all doses examined (fig. 2). However, deprenyl was only selective in its action at 0.03 and 0.1 mg/kg doses; at higher doses (0.3 to 3.0 mg/kg), deprenyl also significantly (P < .05) reduced the deamination of [¹⁴C]-5-HT (type A MAO activity). In a fashion similar to that seen before, the intraneuronal deamination of selectively accumulated [¹⁴C]DA was inhibited within the same concentration of range of deprenyl that caused a significant (P < .05) reduction in the deamination of the type A MAO substrate, [¹⁴C]-5-HT. At doses of deprenyl (0.03 and 0.1 mg/kg) that were selective for type B MAO, [¹⁴C]DA deamination was unaffected.


...both clorgyline and deprenyl were effective in reducing the deamination of newly synthesized [³H]DA; however, this action appeared associated with the reduction in type A MAO activity (fig. 3). For example, at clorgyline concentrations (10^-11 to 10^-7 M) that were highly selective in inhibiting [¹⁴C]-5-HT deamination (type A MAO activity), the formation of [³H]DOPAC and [³H]HVA were similarly inhibited. The same degree of selectivity by deprenyl on [¹⁴C]PEA metabolism (type B MAO activity) was without effect on the deamination of newly synthesized [³H]DA. The formation of [³H]DOPAC and [³H]HVA was only reduced at the highest concentration of deprenyl (0.1 mM) tested. However, this concentration of deprenyl was nonselective and reduced the deamination of [¹⁴C]-5-HT (type A MAO activity) by greater than 80%.
--

Source: Demarest KT, Smith DJ, Azzaro AJ. 1980. The presence of the type A form of monoamine oxidase within nigrostriatal dopamine-containing neurons. J Pharmacol Exp Ther. 1980 Nov, 215(2):461-8. DOWNLOAD

Quotes come from bottom of second column on 463 and bottom of first column on 464.

 

[red22]

Requesting a copy of the following article. Should prove a valuable harm reduction item for anyone considering messing with MAOIs.

Rapid conversion from one monoamine oxidase inhibitor to another
MP Szuba, M Hornig-Rohan, JD Amsterdam
The Journal of Clinical Psychiatry. 08/1997; 58(7):307-10.
DOI: 10.4088/JCP.v58n0704

 

[Abject]

just to clarify, that study was done with L-dep right?

 

[red22]

I hope this is bullshit:


Not only does this effect probably drives some of the toxicity of Selegiline, but the fact that at higher doses Selegiline unselectively inhibits MAO-A is a big no, no. Selegiline can potentially cause hypertension because of MAOA inhibition, something which has pro aging implications. In addition to this side effect, inhibition of MAO-A prevents the induction of anti apoptic proteins, meaning that the less selective higher dose of Selegiline has the possibility of promoting cell death because it makes unavailable the anti apoptic proteins which are neuroprotective.

March, 2, 2013 - anagram - http://www.longecity.org/forum/topi...ine-frowned-upon-here/?view=findpost&p=569311

His references:

Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells.
Inaba-Hasegawa K, Akao Y, Maruyama W, Naoi M.
Journal of Neural Transmission, 2013 Mar, 120(3):435-44. doi: 10.1007/s00702-012-0899-3

Type A and B monoamine oxidase in age-related neurodegenerative disorders: their distinct roles in neuronal death and survival
Naoi M, Maruyama W, Inaba-Hasegawa K
Current Topics in Medicinal Chemistry, 2012, 12(20):2177-88

 

[endotropic]

From the abstract of the second paper he provided:

On the other hand, deprenyl and rasagiline, selective MAO-B inhibitors, have been proved to protect neuronal cells in cellular and animal models of neurodegeneration.